DESCRIPTION: Virtually all ion channels in the nervous system are members of multigene families. This abundance of genes results in a remarkable molecular diversity of both voltage-gated and ligand-gated ion channels. We are using a multidisciplinary approach to study sodium channels (NaChs) which underlie electrical signaling in the nervous system. The proposed research has two goals: (1) to continue identifying and characterizing novel NaCh genes and (2) later to test possible physiological roles subserved by these NaCh subtypes. We estimate that rats (like humans) have at least ten NaCh genes. We have isolated and are characterizing one full-length cDNA and one partial cDNA for novel NaChs. One cDNA is the most abundant NaCh in brain and is expressed in both neurons and glia. The second NaCh is probably expressed only in the peripheral nervous system. We are using a variety of molecular, cellular, and biophysical techniques to study the distribution, abundance, and electrophysiological properties of these NaChs. The second goal centers around a question which has not been answered for any ion channel: why are there so many genes? A simple answer is that all subtypes have similar channel properties but specialized roles. The above studies provide a basis for testing hypothetical roles for these NaCh subtypes. Two functions will be tested: preferential targeting to different cellular domains and differential modulation by second messenger systems. These studies will contribute to our understanding of the molecular components and cellular regulation of Na currents. They also will provide an important foundation for understanding human neural and muscular diseases. Known mutations in the human adult skeletal muscle NaCh gene produce hyperexcitability and sometimes temporary paralysis. It is expected that mutations also occur in the other NaCh genes, most of which are expressed in the nervous system.